Application of a First Impression Triage in the Japan Railway West Disaster

On April 25, 2005, a Japanese express train derailed into a building, resulting in 107 deaths and 549 injuries. We used “First Impression Triage (FIT)”, our new triage strategy based on general inspection and palpation without counting pulse/respiratory rates, and determined the feasibility of FIT in the chaotic situation of treating a large number of injured people in a brief time period. The subjects included 39 patients who required hospitalization among 113 victims transferred to our hospital. After initial assessment with FIT by an emergency physician, patients were retrospectively reassessed with the preexisting the modified Simple Triage and Rapid Treatment (START) methodology, based on Injury Severity Score, probability of survival, and ICU stay. FIT resulted in shorter waiting time for triage. FIT designations comprised 11 red (immediate), 28 yellow (delayed), while START assigned six to red and 32 to yellow. There were no statistical differences between FIT and START in the accuracy rate calculated by means of probability of survival and ICU stay. Overall validity and reliability of FIT determined by outcome assessment were similar to those of START. FIT would be a simple and accurate technique to quickly triage a large number of patients

Description of the Diversity in Surgical Indication and Surgical Strategies for Primary Spinal Cord Tumors: A Nationwide Survey by the Neurospinal Society of Japan

Objective To assess the current management of primary spinal cord tumors (PSCTs) and determine whether and to what extent there are differences in surgical strategies for PSCTs. Methods The Neurospinal Society of Japan conducted a survey between April 1 and 30, 2021. Certified spine surgeons were requested for information on the frequency of surgeries in 2020 and the surgical strategies adopted for each PSCTs. The following tumor histologies were focused: schwannoma, meningioma, and cauda equina tumor as extramedullary tumors; and ependymoma, hemangioblastoma, astrocytoma, and cavernoma as intramedullary tumors. The participants were divided according to their response as follows: experts, who had experienced ≥ 100 surgeries for PSCTs, and nonexperts. Results Among 308 participants (63%), 35 (11%) were experts. The total number of PSCTs in 2020 was 802 of which 564 tumors were extramedullary and 223 were intramedullary. Schwannoma accounted for 53% of the extramedullary tumors, and ependymoma accounted for 39% of the intramedullary tumors. Surgical strategies significantly differed among both the experts and nonexperts groups. Some discrepancies in the adopted surgical strategies were observed between groups. Some of the nonexperts, and none of the experts, ruled out surgery for schwannomas (Eden type 4), astrocytomas, or cavernomas. Five nonexperts (2.2%), and none of the experts, resected the entire dura for meningiomas. Conclusion A nationwide survey revealed that a sufficient consensus did not exist regarding surgical strategies for PSCTs. A disease-specific registry for PSCTs is necessary in academic societies

Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension

Down syndrome (DS) is the most prevalent chromosomal disorder associated with a higher incidence of pulmonary arterial hypertension (PAH). The dysfunction of vascular endothelial cells (ECs) is known to cause pulmonary arterial remodeling in PAH, although the physiological characteristics of ECs harboring trisomy 21 (T21) are still unknown. In this study, we analyzed the human vascular ECs by utilizing the isogenic pairs of T21-induced pluripotent stem cells (iPSCs) and corrected disomy 21 (cDi21)-iPSCs. In T21-iPSC-derived ECs, apoptosis and mitochondrial reactive oxygen species (mROS) were significantly increased, and angiogenesis and oxygen consumption rate (OCR) were significantly impaired as compared with cDi21-iPSC-derived ECs. The RNA-sequencing identified that EGR1 on chromosome 5 was significantly upregulated in T21-ECs. Both EGR1 suppression by siRNA and pharmacological inhibitor could recover the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Alternately, the study also revealed that DYRK1A was responsible to increase EGR1 expression via PPARG suppression, and that chemical inhibition of DYRK1A could restore the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Finally, we demonstrated that EGR1 was significantly upregulated in the pulmonary arterial ECs from lung specimens of a patient with DS and PAH. In conclusion, DYRK1A/PPARG/EGR1 pathway could play a central role for the pulmonary EC functions and thus be associated with the pathogenesis of PAH in DS.Suginobe Hidehiro, Ishida Hidekazu, Ishii Yoichiro, et al. Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension. Human Molecular Genetics 163, 1163 (2023); https://doi.org/10.1093/hmg/ddad162

Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure in children. Despite intensive genetic analyses, pathogenic gene variants have not been identified in most patients with DCM, which suggests that cardiomyocytes are not solely responsible for DCM. Cardiac fibroblasts (CFs) are the most abundant cell type in the heart. They have several roles in maintaining cardiac function; however, the pathological role of CFs in DCM remains unknown. METHODS AND RESULTS: Four primary cultured CF cell lines were established from pediatric patients with DCM and compared with 3 CF lines from healthy controls. There were no significant differences in cellular proliferation, adhesion, migration, ap-optosis, or myofibroblast activation between DCM CFs compared with healthy CFs. Atomic force microscopy revealed that cellular stiffness, fluidity, and viscosity were not significantly changed in DCM CFs. However, when DCM CFs were cocultured with healthy cardiomyocytes, they deteriorated the contractile and diastolic functions of cardiomyocytes. RNA sequencing revealed markedly different comprehensive gene expression profiles in DCM CFs compared with healthy CFs. Several hu-moral factors and the extracellular matrix were significantly upregulated or downregulated in DCM CFs. The pathway analysis revealed that extracellular matrix receptor interactions, focal adhesion signaling, Hippo signaling, and transforming growth factor-β signaling pathways were significantly affected in DCM CFs. In contrast, single-cell RNA sequencing revealed that there was no specific subpopulation in the DCM CFs that contributed to the alterations in gene expression. CONCLUSIONS: Although cellular physiological behavior was not altered in DCM CFs, they deteriorated the contractile and diastolic functions of healthy cardiomyocytes through humoral factors and direct cell–cell contact.Tsuru H., Yoshihara C., Suginobe H., et al. Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy. Journal of the American Heart Association 12, e029676 (2023); https://doi.org/10.1161/JAHA.123.029676

Clinical Outcomes and Genetic Analyses of Restrictive Cardiomyopathy in Children

BACKGROUND: Restrictive cardiomyopathy in children is rare and outcomes are very poor. However, little information is available concerning genotype-outcome correlations. METHODS: We analyzed the clinical characteristics and genetic testing, including whole exome sequencing, of 28 pediatric restrictive cardiomyopathy patients who were diagnosed from 1998 to 2021 at Osaka University Hospital in Japan. RESULTS: The median age at diagnosis (interquartile range) was 6 (2.25-8.5) years. Eighteen patients received heart transplantations and 5 patients were on the waiting list. One patient died while waiting for transplantation. Pathologic or likely-pathogenic variants were identified in 14 of the 28 (50%) patients, including heterozygous TNNI3 missense variants in 8 patients. TNNT2, MYL2, and FLNC missense variants were also identified. No significant differences in clinical manifestations and hemodynamic parameters between positive and negative pathogenic variants were detected. However, 2- and 5-year survival rates were significantly lower in patients with pathogenic variants (50% and 22%) compared with survival in patients without pathogenic variants (62% and 54%; P=0.0496, log-rank test). No significant differences were detected in the ratio of patients diagnosed at nationwide school heart disease screening program between positive and negative pathogenic variants. Patients diagnosed by school screening showed better transplant-free survival compared with patients diagnosed by heart failure symptoms (P=0.0027 in log-rank test). CONCLUSIONS: In this study, 50% of pediatric restrictive cardiomyopathy patients had pathogenic or likely-pathogenic gene variants, and TNNI3 missense variants were the most frequent. Patients with pathogenic variants showed significantly lower transplant-free survival compared with patients without pathogenic variants.Ishida H., Narita J., Ishii R., et al. Clinical Outcomes and Genetic Analyses of Restrictive Cardiomyopathy in Children. Circulation: Genomic and Precision Medicine 16, 382 (2023); https://doi.org/10.1161/CIRCGEN.122.004054

A geochemical clogging model with carbonate precipitation rates under hydrothermal conditions

A step-wise numerical calculation method was developed to provide predictions of when and where carbonate deposits might be found through reservoirs during CO2 sequestration. Flow experiments through porous media using a supersaturated carbonate fluid were also performed in order to observe flow rates. In order to evaluate precipitation rates and permeability change in the formation, calculated flow rates based on the proposed geochemical clogging model were compared with the experimentally observed data. Both high and low temperature cases were studied to understand how hydrothermal conditions can affect precipitation rates of carbonate. According to chemical kinetics, growth rates of minerals are generally proportional to the saturation index (S.I.) that depends on temperature. Thus, a supersaturated fluid has the advantage of improving the filtration and the amount of C fixation (σ). However, when the ratio of filtration coefficient (λ) to pore fluid velocity (u) increases, the permeability around the injection point tends to be significantly reduced by carbonate accumulation, and thus, this might result in insufficient injection of CO2. Therefore, it is essential to understand how to control both λ and u so that the precipitation of carbonate can be located as far away from the inlet as possible

Direct nose-to-brain delivery of diazepam via trigeminal nerve contributes to rapid seizure suppression in pentylenetetrazole-induced status epilepticus model rats

The purpose of our present study was to elucidate the involvement of the direct transfer to the brain after intranasal (i.n.) administration of diazepam (DZP), and to provide findings whether i.n. the administration could be used to obtain rapid onset of pharmacological action. We determined the blood and brain kinetics of DZP after administrations of i.n. and other routes, and the relationship between their concentrations and rapid seizure suppression effect; furthermore, and evaluated the distribution process of DZP to the brain. There was a negative connection between the plasma concentration and the amount of DZP delivery to the brain from the systemic circulation during the period that followed intravenous and intrarectal injection before the onset of seizure suppression. I.n. administration resulted in the seizure suppression time below the correlation curve: the seizure suppression effects were observed earlier than estimated despite the low plasma concentrations of DZP, suggesting the involvement of direct nose-to-brain delivery of DZP. The time to maximum concentration (Tmax) in the forebrain, hindbrain, olfactory bulb (OB), trigeminal nerve (TN), and cerebrospinal fluid (CSF) after i.n. the administration was 3 min, which was shorter than the Tmax of the plasma concentration. In fluorescence imaging using Rhodamin-B-base, the TN and the area of the vicinity of the thalamus had stronger fluorescence 1 and 3 min after i.n. administration, compared with the OB and CSF. In summary, direct brain delivery of DZP requires the TN and it was suggested that distribution to the vicinity of the thalamus via the TN may be connected to the quick seizure suppression effect. Keywords: Status Epilepticus, Diazepam, Intranasal Administration, Nose-to-Brain, Trigeminal Nerv